Self-binding shearform compositions

ABSTRACT

A self-binding, glycerine-free tablettable composition has a saccharide carrier and the sugar alcohols sorbitol and xylitol.

RELATED APPLICATION

This application is a continuation-in-part of U.S. Ser. No. 08/915,068,filed Aug. 20, 1997 U.S. Pat. No. 5,840,334.

FIELD OF THE INVENTION

The compositions of the invention have enhanced cohesive andself-binding properties which permit tableting without added glycerine.They use unique combinations of components, which, when processed usingflash heat yield tabletable masses.

BACKGROUND OF THE INVENTION

Glycerine, a tableting additive, has been used for its ability to lendstickiness to tablet formulations. Some stickiness is desirable, servingto provide cohesion to hold the tablet ingredients together so that theyare flowable and can be processed readily. However, in certainsituations, the use of glycerine can produce too much stickiness,resulting in the formulations clumping or sticking in various machineparts before and during tableting. Self-binding, readily flowablecompositions containing no glycerine have been unknown to the art.

One method for addressing the need for self-binding flowableformulations was the production of shearform matrices or flosses. Thesematrices result when using certain processing techniques, such as thefollowing:

Matrices formed by flash-heat processing are known. U.S. Pat. No.5,429,836, incorporated herein by reference, describes the flash flowprocess and its use to make amorphous solid shearform matrices havingflake-like form.

U.S. Pat. No. 5,587,172, also incorporated herein by reference,discusses the use of flash heat techniques to produce sucrose-containingflosses, which are then processed to yield tablets.

The use of shearform matrices for forming comestible units is describedin WO95/34290 (published Dec. 21, 1995) from co-assigned application No.PCT/US95/07144, filed Jun. 6, 1995. The PCT case discloses a quickdissolving tablet which is formed by: (1) using flash-flow technology toprovide a shearform matrix; (2) combining the partially recrystallizedmatrix with an additive to form flowable, compactable particulateblends; and (3) compacting the blends at relatively low pressure to formcomestible units, such as tablets.

Additionally, PCT publication WO 95/34293 (published Dec. 21, 1995) fromco-assigned PCT Application No. PCT/US95/07194, filed Jun. 6, 1995,discloses a process and apparatus for making rapidly dissolving dosageunits by flash-flow processing. In this PCT application, a shearformmatrix is formed by the flash-flow process, the shearform matrix iscombined with an additive, and the matrix is molded to make a unitdosage form. Tamping may be used to compact the dosage form and increaseits integrity.

SUMMARY OF THE INVENTION

The invention provides matrices to be used in compositions havingimproved tableting properties, compositions containing those matricesand methods of making them.

Applicants have now discovered that, for tablet formulations derivedfrom saccharide-based carriers, the use of a unique combination ofcarrier or feedstock ingredients yields self-binding, flowable matricesand tablet compositions. This combination--which uses a blend of thesugar alcohols sorbitol and xylitol--is superior to glycerine inproviding cohesive properties and flowability. The combination minimizesthe incidence of sticking and clumping problems associated with the useof glycerine in compositions to be tableted. Furthermore, tabletcompositions containing these sugar alcohols are usefull in both high-and low-pressure tableting processes.

The tablet compositions of the invention are based on matrices whichcomprise xylitol and at least one more sugar alcohol, which matricesfall into one of the following groups of matrix systems:

One group is exemplified by a shearform matrix, or floss, containing acarrier and two or more sugar alcohols, one of which is xylitol. This a"single floss" or "unifloss" system.

A second group is exemplified by (I) a first shearform carrier matrixcomprising a carrier and at least one sugar alcohol, generally sorbitol(the "base floss"); and (II) a second shearform binder matrix comprisinga carrier and xylitol (the "binder floss"). This is a "dual floss"system.

Actives and other conventional tablet ingredients can be added, insuitable amounts, to the self-binding shearform matrices of the presentinvention during the production of the matrices and/or after thematrices are collected and chopped, but before tableting.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the parts and percentages used in thespecification are weight percentages, based upon total compositionweight. The terms "matrix" and "floss" are used interchangeably.

The preparation of flosses suitable for use in the present invention isdisclosed in co-assigned patent applications PCT application No.PCT/US95/07144, filed Jun. 6, 1995 and PCT publication WO 95/34293, bothincorporated herein by reference. Preferably, the floss is a "shearformmatrix" produced by subjecting a feedstock which contains a sugarcarrier to flash-heat processing.

In the flash-heat process, the feedstock is simultaneously subjected tocentrifugal force and to a temperature gradient which raises thetemperature of the mass to create an internal flow condition whichpermits part of it to move with respect to the rest of the mass. Theflowing mass exits through openings provided in the perimeter of aspinning head. The temperature gradient is supplied using heaters orother means which cause the mass' temperature to rise. Centrifugal forcein the spinning head flings the internally flowing mass outwardly, sothat it reforms as discrete fibers with changed structures.

An apparatus which produces suitable conditions is a modified flossmaking machine, such as that described in application PCT/US98/09184filed on May 4, 1998, entitled "Apparatus for Melt Spinning FeedstockMaterial having a Flow Restricting Ring". The content of thatapplication is hereby incorporated by reference.

Typically, spinning is conducted at temperatures and speeds of about 180to 250 degrees C and 3,000 to 4,000 rpm, respectively.

Suitable spinner heads include that disclosed in U.S. Pat. No.5,458,823, assigned to Applicants' assignee, which is herebyincorporated by reference.

Other useful apparatuses or processes which provide similar forces andtemperature gradient conditions can be used.

Floss or matrix particles can be chopped using the apparatus discussedin U.S. Pat. No. 5,637,326 or another device having a similar function.

The matrices used herein include a carrier, or feedstock, material whichcarrier material comprises at least one selected from materials whichare capable of undergoing the physical and/or chemical changesassociated with flash heat processing. Useful carriers includecarbohydrates which become free-form particulates when flash heatprocessed. Saccharide-based carriers, including saccharides (i.e.,sugars), polysaccharides and mixtures thereof can be used.

The feedstocks used in the invention can include carriers chosen fromvarious classes of "sugars". "Sugars" are those substances which arebased on simple crystalline mono- and di-saccharide structures, i.e.,based on C₅ and C₆ sugar structures. They can include glucose, sucrose,fructose, lactose, maltose, pentose, arbinose, xylose, ribose, mannose,galactose, sorbose, dextrose and sugar alcohols, such as sorbitol,mannitol, xylitol, maltitol, isomalt, sucralose and the like andmixtures thereof. Sucrose is the preferred sugar.

Useful mixtures of carriers include the sugars listed above along withadditional mono- di-, tri- and polysaccharides. Additional saccharidescan be used in amounts of up to 50% by weight of the total sugar,preferably up to 30%, most preferably up to 20%.

Optionally, the polysaccharides can be used alone as carriers.Polysaccharide carriers include polydextrose and the like. Polydextroseis a non-sucrose, essentially non-nutritive, carbohydrate substitute. Itcan be prepared through polymerization of glucose in the presence ofpolycarboxylic acid catalysts and polyols. Generally, polydextrose iscommercially available in three forms: polydextrose A and polydextroseK, which are powdered solids; and polydextrose N supplied as a 70%solution. Applicants incorporate herein by reference U.S. Pat. No.5,501,858, which discusses polydextrose.

If other carrier materials are used, they are employed in combinationwith sugar and not as total replacement therefor. For example,maltodextrins may be employed. Maltodextrins include mixtures ofcarbohydrates resulting from the hydrolysis of a saccharide. They aresolids having a dextrose equivalent (DE) of up to and including 65.

The carrier can also include maltooligo-saccharides produced byselective hydrolysis of corn starch. A general description ofmaltooligo-saccharides useful herein is set forth in co-owned U.S. Pat.Nos. 5,347,431 and 5,429,836, both incorporated herein by reference.

Applicants use the following types of matrix systems, which systems aredevoid of glycerine.

In the first system, xylitol is added to a mixture of saccharide-basedcarrier and one or more additional sugar alcohols, with sorbitol beingfavored as an additional sugar alcohol. The carrier mix is flash-heatprocessed to provide a shearform floss having self-binding properties.Flosses made using sucrose, sorbitol and xylitol have been found toyield particularly effective self-binding properties. They exemplify"single floss" or "unifloss" systems.

The second system makes separate xylitol-containing binder flosses. Thebinder flosses ("binder portions") are combined with base flosses ("baseportions"), which contain a different sugar alcohol and a saccharide.Preferably, the base floss contains sorbitol and sucrose, while thebinder floss contains xylitol. These are termed "dual floss" systems.

The ingredients which increase cohesiveness and give self-bindingproperties preferably include sugar alcohols, such as sorbitol, xylitol,maltitol, mannitol and mixtures thereof, all of which form flosses.Other sugar alcohols, especially hygroscopic ones, are contemplated.

Xylitol and sorbitol are the preferred sugar alcohols. Effective amountsof xylitol in the flosses are between about 0.5% and 25%, and preferablyabout 10% by weight. Sorbitol is used in the flosses in amounts of about0.5% to about 40%.

When sorbitol and xylitol are used, the ratio of sorbitol to xylitol isfrom about 1:0.1 to about 1:10.

In dual floss systems, about 20 to about 80%, preferably about 34%, ofthe total floss content is xylitol-containing, or binder, floss.Likewise, the sorbitol-containing, or base, floss may be about 20 to 80%of the total floss. In some "dual floss" embodiments, xylitol-containingflosses are first mixed with active ingredient(s), then mixed withsucrose/sorbitol flosses.

Regardless of the number of flosses, the total floss content preferablyincludes about 50 to about 85% sucrose, about 5 to about 20% sorbitoland about 5% to about 25% xylitol.

In some cases, flosses are used along with bio-affecting, or active,microspheres in the tableting process. Often, a xylitol-containing flossis added to microspheres of one or more active agents first and then anon-xylitol-containing floss is added. Typically, the weight ratio oftotal floss to microspheres is about 1:1. In these instances, about 5%to about 25% of the floss is xylitol.

Whereas prior art shearform matrices conventionally included a liquidbinding additive such as glycerine, the present matrices do not.Instead, they get their enhanced cohesiveness, self-binding characterand flowability directly from the matrix or feedstock ingredients andthe processing used.

The amorphous shearform matrix of the present invention is preferablymade from a feedstock which includes sucrose, sorbitol, and xylitol. Asset forth in co-assigned application Ser. No. 08/915,067, filed Aug. 20,1997, U.S. Pat. No. 5,869,098 and entitled "Fast Dissolving ComestibleUnits Formed under High Speed/High Pressure Conditions", thesecompositions promote recrystallization and tableting of thematrix-containing mixes to a level sufficient to provide particulateflowability for use in high speed and high pressure tableting equipment.

Applicants do not wish to be bound by a particular theory. However, theybelieve that a hygroscopic material must be present to provide goodself-binding characteristics to the final matrices and the compositionscontaining them. The hygroscopic material must have a hygroscopicitywhich is substantially higher then that of the carrier carbohydrate(e.g., sucrose) and the non-xylitol sugar alcohol in order to produceand control the self-binding properties. Also, it must be capable ofbeing flash-heat processed along with the carbohydrate component(s).

Applicants theorize that the hygroscopic material is initially presentin the matrix in its amorphous state, but, due to its propensity to pickup moisture, it recrystallizes into a more crystalline structure. Due tothe intimate contact between all components in the matrix, therecrystallization of one component can affect, to some extent, thecharacteristics of surrounding components and the properties of thematrix as a whole. When sufficient recrystallization has occurred in thehygroscopic material and the amorphous material as a whole, the matrixis such that, due the loss of some amorphous character, flowability isenhanced and conventional tableting machinery can be used.

The compositions to be processed into comestible units, or tablets, cancontain conventional additives. Conventional quantities of theseadditives may be incorporated into one or more of the matrices or may bemixed therewith prior to tableting. Useful amounts of conventionaladditives range from about 0.01% to about 80% by weight, based on theweight of the matrices or formulations in which they are used. Thequantities may vary from these amounts, depending on the functions ofthe additives and the characteristics desired in the matrices and/or thefinal tablet compositions.

Conventional tableting aids may be selected from a wide variety ofmaterials such as lubricants, glidants, anti-caking agents and flowagents. For example, lubricants such as adipic acid, magnesium stearate,calcium stearate, zinc stearate, hydrogenated vegetable oils, sodiumchloride, sterotex, polyoxyethylene, glyceryl monostearate, talc,polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesiumlauryl sulfate, sodium stearyl fumarate, light mineral oil and the likemay be employed, with sodium stearyl faimarate preferred. Waxy fattyacid esters, such as glyceryl behenate, sold as "Compritol" products,can be used. Other useful commercial lubricants include "Stear-O-Wet"and "Myvatex TL". Mixtures are operable.

Lubricants are used in amounts ranging from about 0% to about 10%, withabout 0.01% to about 5.0% typically used.

Glidants such as starch, talc, lactose, stearates, dibasic calciumphosphate, magnesium carbonate, magnesium oxide, calcium silicate,Cabosil, Syloid, and silicon dioxide aerogels may be employed.

Glidants are present in amounts ranging from about 0% to about 20%, withamounts of about 0.1% to about 5.0% being typical. Lactose, which may bea glidant or filler, can be added to the chopped floss at about 2%concentration to inhibit clumping.

The preformed matrices produced in accordance herewith may be renderedmore crystalline by one or more of the following crystallizingtechniques. The nature of the matrix feedstock determines whether thematrix is recrystallized after it is formed. Nonetheless,"crystallization" and "recrystallization" are used interchangeablyherein.

One technique for recrystallizing involves the use of crystallizationenhancers. These are used after the floss has been formed, but beforethe floss-containing composition is tableted. Suitable crystallizationenhancers include ethanol, polyvinyl-pyrrolidone, water (e.g. moisture),glycerine, radiant energy (e.g., microwaves) and the like, withcombinations being useful. When they are physical materials, typicalamounts of these enhancers range from about 0.01% to about 10.0% byweight of the tablet composition.

Another technique relates to the use of crystallization modifiers. Thesecrystallization modifiers are floss ingredients, used at levels of about0.01% to about 20.0% by weight of the floss.

Surfactants are preferred crystallization modifiers. Other materialswhich are non-saccharide hydrophilic organic materials may also be used.Useful modifiers preferably have a hydrophilic to lipid balance (HLB) ofabout 6 or more. Such materials include, without limitation, anionic,cationic, and zwitterionic surfactants as well as neutral materials withsuitable HLB values. Hydrophilic materials having polyethylene oxidelinkages are effective. Those with molecular weights of at least about200, preferably at least 400, are highly useful.

Crystallization modifiers useful herein include: lecithin, polyethyleneglycol (PEG), propylene glycol (PPG), dextrose, the SPANS and TWEENSwhich are commercially available from ICI America, and the surfaceactive agents known as "Carbowax". Generally, the polyoxyethylenesorbitan fatty acid esters called TWEENS, or combinations of suchmodifiers are used. Crystallization modifiers are usually incorporatedinto matrices in amounts of between about 0% and 10%.

Optionally, the matrices are allowed to recrystallize, with or withoutadded crystallization modifiers, either before or after they arecombined with the non-matrix component(s), e.g., the bio-affectingadditive(s). When recrystallization occurs before tableting, therecrystallization level of the matrix generally reaches at least about10%. The use of such partially recrystallized matrices leads tocompositions that are free flowing and tabletable using conventionalmachines. U.S. Pat. No. 5,597,416 describes a process for recrystalizingin the presence of additives.

Methods for effecting the recrystallization of the matrices include: useof Tween 80 or other crystallization modifier(s) in the matrix premix;aging of the matrix for up to several weeks, contacting the matrix withsufficient moisture and heat to induce crystallization, and treating thefloss or the floss-containing composition with ethanol or anothercrystallization enhancer. Combinations of these may be used.

When a surfactant, such as a Tween is used, about 0.001% to about 1.00%is included in the floss preblend as a crystallization modifier.Following preblending, the formulations are processed into flosses, thenchopped and used, with or without additives, to make tablets. Mixturesof surfactants can be used.

Aging may be used to recrystallize the matrix or floss. The agingprocess involves a two-step process. First the matrix, which typicallycontains at least one crystallization modifier, is formed, chopped andallowed to stand in closed or sealed containers without fluidization orother agitation under ambient conditions, e.g., at room temperature andatmospheric pressure, for up to several days, preferably for about 1 toabout 3 days. Later, the matrix is mixed, and optionally furtherchopped, with one or more other ingredients. The mix is then aged byallowing it to stand for an additional period of about 1 to about 3days. Generally, the two-step aging process takes a total of about oneweek, with periods of about 4 to about 5 days being typical.

The flosses may also be recrystallized by subjecting them to increasedheat and moisture. This process is similar to aging, but involvesshorter periods of time. Using a fluidized bed apparatus or othersuitable device, chopped floss is fluidized while heating, at ambienthumidity and pressure, to temperatures of about 25° C. to about 50° C.Typically, the temperature is monitored to minimize clumping of flossparticles during this operation. If any clumping occurs, the flossparticles must be sieved before being further processed into tablets.Heating times of about 5 to about 30 minutes are typical.

When ethanol is used as a crystallization enhancer, it is used inamounts, based upon the weight of the matrix, of about 0.1% to about10%, with amounts of about 0.5% to about 8.0% being very effective. Thepreformed matrix is contacted with ethanol. Excess ethanol is evaporatedby drying for about an hour at about 85° F. to about 100° F., with 95°F. being highly useful. The drying step is carried out using traydrying, a jacketed mixer or other suitable method. Following ethanoltreatment, the matrix becomes partially recrystallized on standing for aperiod ranging from about a few hours up to several weeks. When thefloss is about 10 to about 30% recrystallized, it is tableted afterblending with other ingredients. The tableting compositions flow readilyand are cohesive.

Recrystallization of the matrix may take place in the presence of one ormore bio-affecting agents or other additives.

Recrystallization of the matrix can be monitored by measuring thetransmittance of polarized light therethrough or by the use of ascanning electron microscope. Amorphous floss or shearform matrix doesnot transmit polarized light and appears black in the light microscopewhen viewed with polarized light. Using bright field microscopy or thescanning electron microscope, the surface of the floss appears verysmooth. In this condition, it is 0% recrystallized. That is, the flossis 100% amorphous.

Recrystallization of amorphous matrix starts at the surface of the massand can be modified, e.g., accelerated, by the presence ofcrystallization modifiers, as well as moisture. When TWEENS assist therecrystallization, initiation of recrystallization is evidenced by abirefringence observed on the surface of the shearform matrix (floss) asviewed with polarized light. There are faint points of light riddledthroughout the matrix surface. When birefringence appears,recrystallization has begun. At this stage, recrystallization is betweenabout 1% and 5%.

As recrystallizatiion proceeds, the birefringence on the surface of thematrix grows continually stronger and appears brighter. The points oflight grow in size, number and intensity, seeming to almost connect.Using bright field or scanning electron microscopy, the surface of thematrix appears wrinkled. At this point, about 5 to 10% recrystallizationhas occurred.

Surfactant (e.g., TWEEN 80) droplets become entrapped within the matrix.These droplets are obscured as recrystallization proceeds. As long asthey are visible, the floss is generally not more than about 10% to 20%recrystallized. When they are no longer observable, the extent ofrecrystallization is no more than about 50%.

The recrystallization of the matrix results in reduction of the totalvolume of material. Ordered assays of molecules take up less space thandisordered arrays. Since recrystallization begins at the surface of thefloss, a crust is formed which maintains the size and shape of thefloss. There is an increase in the total free volume space within thefloss as recrystallization nears completion, which manifests itself as avoid inside the floss. This is evidenced by a darkened central cavity inlight microscopy and a hollow interior in scanning electron microscopy.At this stage, the floss is believed to be about 50% to about 75%recrystallized.

The intensity of transmitted polarized light increases as the flossbecomes more crystalline. The polarized light can be measured by aphoton detector and assigned a value against calculated standards on agray-scale.

The final observable event in the recrystallization of floss is theappearance of fine, "cat whisker-like" needles and tiny blades whichgrow and project from the surface of the floss. These crystals, believedto be sorbitol (cat whiskers) and xylitol (blades), literally cover thefloss like a blanket of fuzz. These features can be easily recognized byboth light and electron microscopes. Their appearance indicates thefinal stage of recrystallization. The floss is now 100% recrystallized,i.e., substantially non-amorphous.

The matrix portions of the tablettable composition are typically formedvia flash-heat processing into a floss. The floss strands are maceratedor chopped into rods for further processing. Rods of chopped floss havelengths of about 50 to about 500 microns.

When active agents, such as bio-affecting agents, are added, they areoften added in the form of spheroidal particles, and generally asuniform microspheres. Suitable microspheres and other spheroidalparticles can be made by "liquiflash" processes.

"Liquiflash" processing involves the use of heat and pressure to reducethe feedstock to a condition in which resistance to flow, e.g.,viscosity, which impedes the propensity to form liquid droplets, iseliminated. In this condition, the mass has become liquid or"liquiform". Once all resistance to flow is gone, shear force is appliedto the feedstock until discrete particles separate from the mass. Theparticles, called "shearlite" particles, have a size and shapeinfluenced only by natural mass separation of the flowing feedstock.U.S. Pat. Nos. 5,458,823 and 5,683,720, both incorporated herein byreference, show processes and devices for such processing.

The inventive compositions may include one or more active ingredients,such as bio-affecting agents. These are typically prescription or overthe counter medications.

The active ingredients useful herein can be selected from a large groupof therapeutic agents. Respective classes include those in the followingtherapeutic categories: ace-inhibitors; alkaloids; antacids; analgesics;anabolic agents; anti-anginal drugs; anti-allergy agents;anti-arrhythmia agents; antiasthinatics; antibiotics;anticholesterolemics; anticonvulsants; anticoagulants; antidepressants;antidiarrheal preparations; anti-emetics; antihistamines;antihypertensives; anti-infectives; anti-inflammatories; antilipidagents; antimanics; anti-migraine agents; antinauseants; antipsychotics;antistroke agents; antithyroid preparations; anabolic drugs; antiobesityagents; antiparasitics; antipsychotics; antipyretics; antispasmodics;antithrombotics; antitumor agents; antitussives; antiulcer agents;anti-uricemic agents; anxiolytic agents; appetite stimulants; appetitesuppressants; beta-blocking agents; bronchodilators; cardiovascularagents; cerebral dilators; chelating agents; cholecystekininantagonists; chemotherapeutic agents; cognition activators;contraceptives; coronary dilators; cough suppressants; decongestants;deodorants; dermatological agents; diabetes agents; diuretics;emollients; enzymes; erythropoietic drugs; expectorants; fertilityagents; fungicides; gastrointestinal agents; growth regulators; hormonereplacement agents; hyperglycemic agents; hypoglycemic agents;ion-exchange resins; laxatives; migraine treatments; mineralsupplements; mucolytics, narcotics; neuroleptics; neuromuscular drugs;non-steroidal anti-inflammatories (NSAIDs); nutritional additives;peripheral vasodilators; polypeptides; prostaglandins; psychotropics;renin inhibitors; respiratory stimulants; sedatives; steroids;stimulants; sympatholytics; thyroid preparations; tranquilizers; uterinerelaxants; vaginal preparations; vasoconstrictors; vasodilators; vertigoagents; vitamins; wound healing agents; and others.

Active agents which may be used in the invention include: acetaminophen;acetic acid; acetylsalicylic acid, including its buffered forms;acrivastine; albuterol and its sulfate; alcohol; alkaline phosphatase;allantoin; aloe; aluminum acetate, carbonate, chlorohydrate andhydroxide; alprozolam; amino acids; aminobenzoic acid; amoxicillin;ampicillin; amsacrine; amsalog; anethole; ascorbic acid; aspartame;astemizole; atenolol; azatidine and its maleate; bacitracin; balsamperu; BCNU (carmustine); beclomethasone diproprionate; benzocaine;benzoic acid; benzophenones; benzoyl peroxide; benzquinamide and itshydrochloride; bethanechol; biotin; bisacodyl; bismuth subsalicylate;bornyl acetate; bromopheniramine and its maleate; buspirone; caffeine;calamine; calcium carbonate, casinate and hydroxide; camphor; captopril;cascara sagrada; castor oil; cefaclor; cefadroxil; cephalexin;centrizine and its hydrochloride; cetyl alcohol; cetylpyridiniumchloride; chelated minerals; chloramphenicol; chlorcyclizinehydrochloride; chlorhexidine gluconate; chloroxylenol;chloropentostatin; chlorpheniramine and its maleates and tannates;chlorpromazine; cholestyramine resin; choline bitartrate; chondrogenicstimulating protein; cimetidine and its hydrochloride; cinnamedrinehydrochloride; citalopram; citric acid; clarithromycin; clemastine andits fiumarate; clonidine and its hydrochloride salt; clorfibrate; cocoabutter; cod liver oil; codeine and its fumarate and phosphate; cortisoneacetate; ciprofloxacin HCl; cyanocobalamin; cyclizine hydrochloride;cyproheptadine and its hyddrochloride; danthron; dexbromopheniraminemaleate; dextromethorphan and its hydrohalides; diazepam; dibucaine;dichloralphenazone; diclofen and its alkali metal sales; diclofenacsodium; digoxin; dihydroergotamine and its hydrogenates/mesylates;diltiazem; dimethicone; dioxybenzone; diphenhydramine and its citrate;diphenhydramine and its hydrochloride; divalproex and its alkali metalsalts; docusate calcium, potassium, and sodium; doxycycline hydrate;doxylamine succinate; dronabinol; efaroxan; enalapril; enoxacin;ergotamine and its tartrate; erythromycin; estropipate; ethinylestradiol; ephedrine; epinephrine bitartrate; erythropoietin;eucalyptol; famotidine; fenoprofen and its metal salts; ferrousfumarate, gluconate and sulfate; fluoxetine; folic acid; fosphenytoin;5-fluorouracil (5-FU); fluoxetine and its hydrochloride; flurbiprofen;furosemide; gabapentan; gentamicin; gemfibrozil; glipizide; glycerine;glyceryl stearate; granisetron and its hydrochloride; griseofulvin;growth hormone; guafenesin; hexylresorcinol; hydrochlorothiazide;hydrocodone and its tartrates; hydrocortisone and its acetate;8-hydroxyquinoline sulfate; hydroxyzine and its pamoate andhydrochloride salts; ibuprofen; indomethacin; inositol; insulin; iodine;ipecac; iron; isosorbide and its mono- and dinitrates; isoxicam;ketamine; kaolin; ketoprofen; lactic acid; lanolin; lecithin; leuprolideacetate; lidocaine and its hydrochloride salt; lifinopril; liotrix;loratadine; lovastatin; luteinizing hormore; LHRH (lutenizing hormonereplacement hormone); magnesium carbonate, hydroxide, salicylate, andtrisilicate; meclizine and its hyddrochloride; mefenamic acid;meclofenamic acid; meclofenamate sodium; medroxyprogesterone acetate;methenamine mandelate; menthol; meperidine hydrochloride; metaproterenolsulfate; methscopolamine and its nitrates; methsergide and its maleate;methyl nicotinate; methyl salicylate; methyl cellulose; methsuximide;metoclopramide and its halides/hydrates; metronidazole and itshydrochloride; metoprotol tartrate; miconazole nitrate; mineral oil;minoxidil; morphine; naproxen and its alkali metal sodium salts;nifedipine; neomycin sulfate; niacin; niacinamide; nicotine;nicotinamide; nimesulide; nitroglycerine; nonoxynol-9; norethindrone andits acetate; nystatin; octoxynol; octoxynol-9; octyl dimethyl PABA;octyl methoxycinnamate; omega-3 polyunsaturated fatty acids; omeprazole;ondansetron and its hydrochloride; oxolinic acid; oxybenzone;oxtriphylline; para-aminobenzoic acid (PABA); padimate-O;paramethadione; pentastatin; peppermint oil; pentaerythritoltetranitrate; pentobarbital sodium; perphenazine; phenelzine sulfate;phenindamine and its tartrate; pheniramine maleate; phenobarbital;phenol; phenolphthalein; phenylephrine and its tannates andhydrochlorides; phenylpropanolamine and its hydrochloride salt;phenytoin; pirmenol; piroxicam and its salts; polymicin B sulfate;potassium chloride and nitrate; prazepam; procainamide hydrochloride;procaterol; promethazine and its hydrochloride; propoxyphene and itshydrochloride and napsylate; pramiracetin; pramoxine and itshydrochloride salt; prochlorperazine and its maleate; propanolol and itshydrochloride; promethazine and its hydrochloride; propanolol;pseudoephedrine and its sulfates and hydrochorides; pyridoxine;pyrolamine and its hydrochlorides and tannates; quinapril; quinidinegluconate and sulfate; quinestrol; ralitoline; ranitadine; resorcinol;riboflavin; salicylic acid; scopolamine; sesame oil; shark liver oil;simethicone; sodium bicarbonate, citrate, and fluoride; sodiummonofluorophosphate; sucralfate; sulfanethoxazole; sulfasalazine;sulfur; sumatriptan and its succinate; tacrine and its hydrochloride;theophylline; terfenadine; thiethylperazine and its maleate; timolol andits maleate; thioperidone; tramadol; trimetrexate; triazolam; tretinoin;tetracycline hydrochloride; tollmetin; tolnaftate; triclosan;trimethobenzamide and its hydrochloride; tripelennamine and itshydrochloride; tripolidine hydrochloride; undecylenic acid; vancomycin;verapamil HCl; vidaribine phosphate; vitamins A, B, C, D, B₁, B₂, B₆,B₁₂, E, and K; witch hazel; xylometazoline hydrochloride; zinc; zincsulfate; zinc undecylenate. Mixtures and pharmaceutically acceptablesalts of these and other actives can be used.

Particularly useful active agents are sparingly soluble solid agentswhose dissolution and release properties are enhanced by thesolubilizing agents used herein. These agents include H₂ antagonists,analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs),anticholestero-lemics, anti-allergy agents, and anti-migraine agents.

Analgesics include aspirin, acetaminophen, acetaminophen plus caffeine,tramadol and non-steroidal anti-inflammatory drugs (NSAIDS), e.g.,ibuprofen and nimesulide.

Useful NSAIDs include ibuprofen; diclofenac and its alkali metal salts;fenoprofen and its metal salts; fluriprofen; ketoprofen; naproxen andits alkali metal salts; nimesulide; and piroxicam and its salts.

H₂ -antagonists which are contemplated for use in the present inventioninclude cimetidine, ranitidine hydrochloride, famotidine, nizatidine,ebrotidine, mifentidine, roxatidine, pisatidine and aceroxatidine.

Useful anti-allergy agents include hydricodone and its tartrates;clemastine and its fumarate; azatadine and its maleate; acetaminophen;hydroxyzine and its pamoate and hydrochloride salts; chlorpheniramineand its maleates and tannates; pseudoephedrine and its sulfates andhydrochlorides; bromopheniramnine and its maleate; dextromethorphan andits hydrohalides; loratadine; phenylephrine and its tannates andhydrochlorides; methscopolamine and its nitrates; phenylpropanolamineand its hydrochlorides; codeine and its hydrochloride; codeine and itsphosphate; terfenadine; acrivastine; astemizole; cetrizine and itshydrochloride; phenindamine and its tartrate; tripelennamine and itshydrochloride; cyproheptadine and its hydrochloride; promethazine andits hydrochloride; and pyrilamine and its hydrochlorides and tannates.

Useful antimigraine agents include divalproex and its alkali metalsalts; timolol and its maleate; propanolol and its hydrohalides;ergotamine and its tartrate; caffeine; sumatriptan and its succinate;dihydroergotamine, its hydrogenates/mesylates; methsergide and itsmaleate; isometheptene mucate; and dichloralphenazone.

Another class of drugs which can be used are antiemetics. Usefulantiemetics include: meclizine and its hydrochloride; hydroxyzine andits hydrochloride and pamoate; diphenhydramine and its hydrochloride;prochlorperazine and its maleate; benzquinamide and its hydrochloride;granisetron and its hydrochloride; dronabinol; bismuth subsalicylate;promethazine and its hydrochloride; metoclopramide and itshalides/hydrates; chlorpromazine; trimethobenzamide and itshydrochloride; thiethylperazine and its maleate; scopolamine;perphenazine; and ondansetron and its hydrochloride.

Other active ingredients for use in the present invention includeantidiarrheals such as immodium AD, antihistamines, antitussives,decongestants, vitamins, and breath freshners. Also contemplated for useherein are anxiolytics such as Xanax; antipsychotics such as Clozariland Haldon; antihistamines such as Seldane, Hismanal, Relafen, andTavist; antiemetics such as Kytril and Cesamet; bronchodilators such asBentolin, Proventil; antidepressants such as Prozac, Zoloft, and Paxil;antimigranes such as Imigran, ACE-inhibitors such as Vasotec, Capotenand Zestril; Anti-Alzheimers agents such as Nicergoline; andCa^(II),-Antagonists such as Procardia, Adalat, and Calan.

Among the anticholesterolemics, the statins, e.g., lovastatin,provastatin and the like are notable.

Combinations of various types of drugs, as well as combinations ofindividual drugs, are contemplated.

Products which dissolve readily after little or no chewing and hydrationin the mouth can be made using the compositions of the invention. Suchproducts typically contain antacids (e.g., calcium carbonate with andwithout other active agents), one or more vitamins (e.g., Vitamin C orVitamin D), and/or analgesics, such as NSAIDs (e.g., aspirin, ibuprofenor nimesulide).

Other ingredients which may be included are fillers, fragrances, dyes,flavors, sweeteners (both artificial and natural), and otherconventional tablet additives.

For example, fillers may be used to increase the bulk of the tablet.Some of the commonly used fillers are calcium sulfate, both di- andtri-basic; starch; calcium carbonate; microcrystalline cellulose;modified starches, lactose, sucrose; mannitol and sorbitol.

Flavors may be chosen from natural and synthetic flavoring liquids. Anillustrative list of such agents includes volatile oils, syntheticflavor oils, flavoring aromatics, oils, liquids, oleoresins and extractsderived from plants, leaves, flowers, fruits, stems and combinationsthereof. A non-limiting list of these includes citric oils, such alemon, orange, grape, lime and grapefruit an fruit essences, includingapple, pear, peach, grape, strawberry, raspberry, cherry, plum,pineapple, apricot, or other fruit flavors.

Other useful flavorings include aldehydes and esters, such asbenzaldehyde (cherry, almond); citral, i.e., alpha-citral (lemon, lime);neral, i.e., beta-citral (lemon, lime); decanal (orange, lemon);aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehydeC-12 (citrus fruits); tolyl aldehyde (cherry, almond);2,6-dimethyloctanal (green fruit); 2-dodedenal (citrus, mandarin);mixtures thereof and the like.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and mixturesthereof (when not used as a carrier); saccharin and its various salts,such as the sodium salt; dipeptide sweeteners such as aspartame;dihydro-chalcone compounds, glycyrrhizin; Stevia Rebaudiana(Stevioside); chloro derivatives or sucrose such as sucralose; and sugaralcohols such as sorbitol, mannitol, xylitol, and the like. Alsocontemplated are hydrogenated starch hydrolysates and the syntheticsweeteners such as3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof. Other sweeteners may also be used.

Some embodiments include an effervescent disintegration agent to aid inmasking the objectional taste of active ingredients, such as vitamins,medicines and/or minerals, etc. The positive organoleptic sensationachieved by the effervescent action in the mouth, as well as thetexture, speed and sensation of disintegration, aid in maskingundesirable flavor notes.

"Effervescent" refers to those agents which evolve gas. The gas- orbubble-generating action is often the result of the reaction of asoluble acid source and a carbonate source. The reaction of these twogeneral classes of compounds produces carbon dioxide gas upon contactwith water in saliva. Useful acids include: citric, tartaric, malic,fuimaric, adipic, succinic and acid salts and anhydrides thereof. Acidsalts may also include sodium dihydrogen phosphate, disodium dihydrogenpyrophosphate, acid citrate salts and sodium acid sulfite. While thefood acids can be those indicated above, acid anhydrides of theabove-described acids may also be used. Carbonate sources include drysolid carbonate and bicarbonate salts such as sodium bicarbonate, sodiumcarbonate, potassium bicarbonate and potassium carbonate, magnesiumcarbonate and sodium sesquicarbonate, sodium glycine carbonate, L-lysinecarbonate, arginine carbonate and amorphous calcium carbonate. Mixturesof various acid and carbonate sources, as well as other sources ofeffervescence, can be used.

The effervescent agent can be included in at least three different ways.The first method includes incorporating the entire effervescent agent inthe feedstock which is used to form the shearform product. The secondinvolves adding the agent to an already formed shearform matrix. Thethird method incorporates one portion of the agent in the shearformmatrix and adds another portion after formation of the matrix material.The artisan can determine the best way to use the agent for itseffervescent properties.

Other ingredients include binders which contribute to the ease offormation and general quality of the tablet. Binders include starches,pregelatinized starches, gelatin, polyvinylpyrrolidone, methylcellulose,sodium carboxymethylcellulose, ethylcellulose, polyacrylamides,polyvinyloxoazolidone and polyvinylalcohols.

Color additives can be used in preparing tablets. Such color additivesinclude food, drug and cosmetic colors (FD&C), drug and cosmetic colors(D&C) or external drug and cosmetic colors (Ext. D&C). These colors aredyes, lakes, and certain natural and derived colorants. Useful lakesinclude dyes absorbed on aluminum hydroxide or other suitable carriers.

An optional feature involves microspheres which are components ofsubstrate/coating systems. The substrate can be a non-active ingredient,such as a saccharide-based material, or it can be an active or acombination of actives. In one embodiment, the substrates are sugarshearlite particles having active agents coated thereon. The coating mayinclude other types of coating materials, e.g., coloring agents.Additional coatings can be used.

Other useful substrate/coating systems employ substrates which areshearlite particles containing one or more actives. Coatings thereon cancontain saccharides and other ingredients.

Controlled release coatings, e.g., sustained release coatings, are amongthe preferred types of coatings for use in dosage forms which includebio-affecting agents.

Using the invention, strong, highly attractive dosage units, e.g,tablets, can be produced having textures and internal structures whichare relatively open to solubilization. Applicants' compositions aregenerally formed into tablets at pressures of from about 500 up to about6,000 psi. These tablets have initial hardness values of about 0.5 toabout 6.0 pounds (lbs), with 1.0 to 4.0 lbs preferred.

The following non-limiting examples illustrate the invention.

EXAMPLE I Ibuprofen Microspheres

Ibuprofen was processed into spheres as follows:

An ibuprofen powder feedstock was fed to a 5-inch spinning headdisclosed in a U.S. Ser. No. 08/874,215, filed Jun. 13, 1997, entitled"A Spinner Head having Flow Restricting Inserts". The head was rotatedat about 3600 rpm while the heating elements were raised to atemperature which produced the liquiflash conditions. The feedstock alsocontained 10% Compritol 888 ATO and 2% Gelucire 50/13. (Compritol 888ATO is glycerol behenate NF, a lipophilic additive from Gattefosse S.A.,a French company. Gelucire, a polyethylene glycol 32 glyceryl estersolubility enhancer, is also available from Gattefosse.)

After exiting the spinning head, the material was permitted to free falla distance of from 6 to 8 feet below the head. The product consists ofspheres having a highly consistent particle size, with diameters rangingfrom about 50 to 200 microns.

The product was subjected to testing to determine the time required fordissolution of the active ingredient. The monograph is provided by theU.S. Pharmacopeial Convention, Inc. in the U.S. Pharmaceopoeial Nationalformulary Monograph for Ibuprofen Dissolution Study, U.S. 23 NF 18, page786 (1995). At a composition level of 88% ibuprofen, the time fordissolution of most of the ibuprofen was about 15 minutes. Virtualytotal dissolution occurred at around 20 to 25 minutes. These resultsshow high predictability for delivery using these microspheres.

EXAMPLE II Acetaminophen Microspheres

In this example, acetaminophen was processed using a 60 mesh screenpositioned in serpentine fashion between heating elements. Acetaminophenpowder (melting point 169-170.5° C.) was fed to a spinning head run atabout 3600 rpm. While the feedstock was subjected to centrifugal force,the temperature was raised until the acetaminophen powder was reduced toliquiform. The force generated by the spinning head expelledacetaminophen out of the spinner head, and impelled it through the 60mesh screen. The product was permitted to free fall below the head, adistance of about 6 to 8 feet.

Fine spheres, all smaller than about 420 microns in diameter, wereformed. 4.33 kilograms of the spheres passed through a 40 mesh screenand 1.39 kilograms were retained.

EXAMPLE III Tablet Composition containing 10% Xylitol

A. Preparation of Sucrose/Sorbitol Base Floss

The base floss was prepared from a mixture of 84.75 parts sucrose, 15.0parts sorbitol, and 0.25 parts of TWBEN 80. The mix was flash flowprocessed in a device described in U.S. Ser. No. 08/854,344, filed May12, 1997. Two kilograms of this material was spun under ambientconditions of 60° F. and 35% relative humidity. Spinning was conductedat 3600 rpm (60 Hz). The spun floss was collected and chopped in a mixerfor about 45 seconds.

B. Preparation of Xylitol/Sucrose/Sorbitol Binder Floss

A mixture of 74.75 parts of sucrose, 15 parts xylitol, 10 parts sorbitoland 0.25 parts TWEEN 80 was prepared. Two kilograms of this material wasspun into a floss under ambient conditions of 67° F. and 40% relativehumidity at 3600 rpm (60Hz) using a 5 inch plate head as described aboveand chopped in a high shear mixer/chopper for 0.5 minutes.

357.6 grams of acetaminophen (APAP) beads made by the process describedin Example II were placed in a Hobart blender bowl. Chopped binder floss(72.0 grams, sieved through 20 mesh) was added to the beads in theHobart bowl and mixed for 2 minutes. The mix passed through 20 meshsieve after mixing. 272.0 grams of sucrose/sorbitol base floss was addedin 25% increments. With the last 25% increment, flavors (1.8 grams ofcitric acid, 1.983 grams of Alpine creme, 1.8 grams of lemon juice, and4.82 grams of aspartame) were added. Each addition was mixed for 30seconds. This mixture was further blended. The flowability of the tabletblend was measured, resulting in an angle of rupture of 80° and an angleor repose of 55°. This preparation flowed freely. To this mixture wasadded 0.1% of Syloid. The final blend was tableted on a Stokes D-3tablet press at settings which provided a 1.2 g. tablet with an initialhardness of 1 lb.

The ingredients are summarized as follows:

    ______________________________________                                        Saccharide (Base) Floss                                                         Sucrose            84.75 g                                                    Sorbitol           15.00 g                                                    TWEEN 80            0.25 g                                                       Xylitol (Binder) Floss                                                     Sucrose            74.75 g                                                    Xylitol          15.00                                                        Sorbitol           10.00 g                                                    TWEEN 80             0.25 g                                                   Tablet Composition -                                                           10% Xylitol in Total Composition                                             Citric Acid          1.80 g                                                   Alpine creme         1.80 g                                                   Lemon juice          1.80 g                                                   Aspartame           4.80 g                                                    APAP              340.9 g                                                     Chopped floss*     368.9 g                                                                                 720.0 g (total)                                ______________________________________                                         *The floss contained 15% sorbitolcontaining base floss and 85%                xylitolcontaining binder floss.                                          

EXAMPLE IV Preparation of 16% Xylitol Composition

Using the flosses and mixing procedures of Example III, a 16% xylitolcomposition was prepared and tableted at 80 and 100 psi with 0.3 secondsdwell time.

    ______________________________________                                           The tablet composition was:                                            

    ______________________________________                                           Citric acid                  1.81 g                                          Alpine creme          1.83 g                                                  Lemon Juice           1.80 g                                                  Aspartame             4.84 g                                                  APAP               340.00 g                                                   Chopped floss**   368.00 g                                                                          720.00 g (total)                                      ______________________________________                                         **The chopped floss had a 1:0.57 ratio of sorbitol base floss to xylitol      binder floss.                                                            

EXAMPLE V Preparations with 25%, 34% and 100% Xylitol Floss in FinalBlend

This example illustrates tablet compositions containing varying amountsof xylitol-containing (binder) floss.

    ______________________________________                                        Sorbitol (Base) Floss                                                         ______________________________________                                                      Sucrose           84.75 g                                         Sorbitol           15.00 g                                                    TWEEN 80             0.25 g                                                 ______________________________________                                    

2 kilograms of the material was spun under ambient conditions of 66° F.and 38% relative humidity. It was spun at 3600 rpm, as described inExample III, and chopped.

    ______________________________________                                        Xylitol (Binder) Floss                                                          Sucrose             69.75 g                                                   Xylitol             25.00 g                                                   Sorbitol            10.00 g                                                   TWEEN 80              0.25 g                                                2 kg of this mix was spun at 67-68° F.,                                  3600 rpm on a 5 inch head and chopped.                                             A. 25% Xylitol Floss                                                   A 25% xylitol floss containing preparation                                      was made using the following ingredients:                                          Citric acid                 1.83 g                                       Alpine creme           1.80 g                                                 Lemon juice            1.82 g                                                 Aspartame              4.84 g                                                 APAP                353.88 g                                                  Sorbitol floss        61.12 g                                                 Xylitol floss       294.80 g                                                  Cab-o-sil               0.36 g                                                                         720.43 g (total)                                   ______________________________________                                    

The APAP and 55% of the xylitol binder floss (sieved through a 20 meshsieve) were mixed. The remaining binder floss and the sorbitol/sucrosefloss were mixed by hand and sieved through a 20 mesh sieve. This mixwas added in 25% increments to binder floss/APAP mixture. With the lastincrement, the citric acid, Alpine creme, lemon juice and aspartame wereadded.

From this mixture, 10 grams were removed and mixed with the Cab-o-silend. The bulk tableting blend was mixed for 30 seconds, then wastableted on a Stokes D-3 tablet press using the settings from ExampleIII.

    ______________________________________                                        B. 34% Xylitol Floss                                                            The 34% formulation was made from the following ingredients:                ______________________________________                                        Citric acid          1.82 g                                                     Alpine creme         1.81 g                                                   Lemon juice           1.81 g                                                  Aspartame            4.80 g                                                   APAP                353.88 g                                                  Sorbitol floss       111.12 g                                                 Xylitol floss        244.80 g                                                 Cabosil              0.36 g                                                    720.00 g (total)                                                           ______________________________________                                    

Using procedures similar to those employed in Example III, theformulation was tableted.

    ______________________________________                                        C. 100% Xylitol Floss                                                           The following formulation of 100% xylitol binder floss was prepared:        ______________________________________                                        Citric acid                    1.82 g                                           Alpine creme           1.81 g                                                 Lemon juice             1.81 g                                                Aspartame              4.80 g                                                 APAP                353.88 g                                                  Cabosil                0.36 g                                                 Xylito1 floss        355.92 g                                                  720.4 g (total)                                                            ______________________________________                                    

Using procedures similar to those in Example III, the blend was mixedand tableted.

EXAMPLE VI Unifloss

Using a procedure similar to that of Example I, ibuprofen microsphereswere made from a formulation containing 88% ibuprofen, 10% Compritol and2% Gelucire.

Using a process similar to that used in example IIIB, a floss was madefrom the following: 78.25% sucrose, 11.0% sorbitol, 10.0% xylitol and0.75% TWEEN.

The microspheres and floss were then admixed used in the followingcomposition:

    ______________________________________                                        Microspheres            34.4%                                                   Floss                     62.7%                                               Citric acid                0.7%                                               Lemon flavor               0.4%                                               Whipped cream flavor       0.3%                                               Syloid 244 FP              0.5%                                               Sodium stearyl fumarate    1.0%                                             ______________________________________                                    

The floss preblend was processed using the 5" crown head disclosed inU.S. Ser. No. 08/854,344, filed May 12, 1997, U.S. Pat. No. 5,834,033,at 250° C. and rotational speed of 60 Hz (3600 rpm). The floss collectedwas chopped in a Littleford FKM600 mixer with lactose (2% based on theweight of floss) for 2 minutes at 100 rpm. 200 proof ethanol (0.5% basedon floss weight) was sprayed onto the chopped floss and mixed. The flosswas then dried at 40-45° C. for 60 to 90 minutes with intermittentmixing. The dried floss was screened through a 20 mesh screen. Thescreened floss was blended with ibuprofen microspheres in the Littlefordmixer for 5 minutes. To this mix, flavors and flow agents were added andblended for another 2 minutes. Lastly, the lubricant (sodium laurylsulfate) was added and blended for an additional 2 minutes. The blendwas then tableted on a Kilian T200 rotary press using 15 mm roundflat-faced radial edge punches. The tablet weight was maintained at 750mg and hardness was 1.0 to 4.0 lb.

EXAMPLE VII Reduced Xylitol Floss

Using the procedure of Example I, ibuprofen microspheres were made froma formulation containing 88% ibuprofen, 10% Compritol and 2% Gelucire.Via a single floss process similar to that of Example VI, a floss wasmade from the following composition: 83.25% sucrose, 11.0% sorbitol,5.0% xylitol and 0.75% TWEEN.

The microspheres and floss were used in the following composition:

    ______________________________________                                           Microspheres         34.4%                                                   Floss                      62.7%                                              Citric acid                 0.7%                                              Lemon flavor                0.4%                                              Whipped cream flavor        0.3%                                              Syloid 244 FP                 0.5%                                            Sodium stearyl fumarate    1.0%                                             ______________________________________                                    

The ingredients were mixed and the mix was tableted using procedures asdescribed in Example VI.

EXAMPLE VIII Low Compression Tableting

Using the procedure described in Example VI, a floss was produced fromthe following composition:

    ______________________________________                                               Sorbitol       11.0%                                                     Xylitol                  10.00%                                               Sucrose                  78.75%                                               TWEEN 80                  0.25%.                                            ______________________________________                                    

The floss was then combined with microspheres made in accordance withExample I and other ingredients in a tablet composition. The tabletcomposition was:

    ______________________________________                                           Floss                64.1%                                                   Ibuprofen microspheres    34.4%                                               Citric acid                0.7%                                               Lemon flavor               0.4%                                               Whipped cream flavor       0.3%                                               CAB-O-SIL                  0.1%                                             ______________________________________                                    

The mixture was tableted, at a rate of about 15,000 to 20,000 tabletsper hour, using the low compression tableting apparatus described inItalian patent application No. B096A 000453 (attorney docket#0004.ITAL), filed Sep. 11, 1996 and entitled "Meto Do E Macchina Per LaProduzione Di Pasti Glie Di Polvere Medicinale" ("Method and Machine forTablet Production of Medicine Powder"). The disclosure of thatapplication is hereby incorporated by reference. The resultant tabletsweighed 750 grams and had initial hardness values of 1 lb.

U.S. Pat. Nos. 5,653,926 and 5,662,849, all incorporated herein byreference, describe useful processes for making comestible units, suchas tablets.

There have been described what are presently believed to be thepreferred embodiments of the invention. Those skilled in the art willrealize that changes and modifications may be made thereto withoutdeparting from the spirit of the invention, and it is intended to claimall such changes and modifications as fall within the true scope of theinvention.

We claim:
 1. A self-binding glycerine-free tabletable composition comprising:a shearform matrix having enhanced self-binding characteristics consisting essentially of at least one saccharide carrier and at least two sugar alcohols, comprising sorbitol and about 0.5% to about 25% by weight of xylitol which matrix has been treated with at least one crystallization modifier.
 2. The composition of claim 1 wherein the ratio of sorbitol to xylitol is about 1:0.1 to about 1:10 and the carrier is selected from: sucrose, a polysaccharide and mixtures thereof.
 3. The composition of claim 1 wherein the carrier is sucrose.
 4. The composition of claim 3 wherein the crystallization modifier is ethanol.
 5. The composition of claim 1 wherein the crystallization modifier is ethanol.
 6. The composition of claim 1 wherein the carrier is sucrose.
 7. The composition of claim 1 further including a bio-affecting agent in the form of microspheres.
 8. The composition of claim 7 wherein the bio-affecting agent is selected from the group consisting oft acetaminophen, ibuprofen, aspirin and mixtures thereof.
 9. The composition of claim 8 wherein the crystallization modifier is ethanol.
 10. The composition of claim 9 further comprising lactose.
 11. The composition of claim 10 containing: 34.4% ibuprofen microspheres, 62.7% sugar/sorbitol/xylitol matrix, 0.7% citric acid, 0.4% lemon flavor, 0.3% whipped cream flavor, and 0.5% silicon dioxide.
 12. The composition of claim 11 wherein the ibuprofen microspheres are produced from a composition containing: 88% ibuprofen, 10% glyceryl behenate, and 2% polyethylene glycol glyceryl ester.
 13. The composition of claim 12 wherein the matrix contains: 78.25% sucrose, 11.0% sorbitol, 10.0% xylitol, and 0.75% polyoxyethylene sorbitan fatty acid ester.
 14. The composition of claim 1 wherein the matrix contains: 83.25% sucrose, 11.0% sorbitol, 5.0% xylitol and 0.75% polyoxyethylene sorbitan fatty acid ester. 